11 Pathogenesis of Acute Coronary Syndromes: The integral role of plateletsPlaqueFissure or RupturePlateletAdhesionPlateletActivationThromboticOcclusionPlateletAggregationPlatelets are recognized to play an integral role in acute coronary syndromes and arterial thrombosis. After plaque fissure or rupture, there is platelet adhesion and activation. This leads to platelet aggregation within the coronary artery, and ultimately partial or complete occlusion of the coronary artery.Few SMCsActivated MacrophagesInflammatory Cells

17 75 mg of aspirin per day results in almost complete inhibition of cyclooxygenase activity in platelets. This slide demonstrates that high doses of aspirin are no more effective than medium or low doses in reducing the odds of vascular events. Trials using doses of <75mg are less conclusive and, therefore, the available evidence supports daily doses of aspirin in the mg range.

22 PCI-CURE Decessi/IMA in 2658 pazienti sottopostia PTCA nello studio CURE0.1512.6%Placebo+ ASA*0.108.8%PercentualeClopidogrel+ ASA*0.0531% RRRP = N = 2658Prospectively designed study of patients undergoing PCI who were randomized to double-blind therapy with clopidogrel or placebo, both in addition to aspirin and other standard therapy in the CURE trial.Objectives:to test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCIto determine if long-term treatment (up to 1 year) with clopidogrel after PCI would provide additional clinical benefit.For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapy resulted in a 31% RRR (8.8% clopidogrel vs. 12.6% placebo, P = 0.002).The curves diverged early and continued to separate over the course of 12 months.This end point included events that were prevented prior to PCI, in addition to those following the procedure.There were consistent reductions in MI or cardiovascular death in almost every subgroup examined0.0100200300400Giorni di follow up* In combination with standard therapy Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

23 The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin ( mg) or aspirin ( mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint was stroke, myocardial infarction, or death from cardiovascular causes. The primary end point occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046).

34 Statins administration in primary and secondary preventionPre-clinical CHD Chronic CHDACSSecondary prevention4S /HPS (sim mg)CARE /LIPID (pra 40 mg)LIPS (flu 80 mg)TNT/IDEAL (ato > mg)Primary preventionAFCAPS (lov mg)WOSCOPS (pra 40 mg)ASCOT/ CARDS (ato 10 mg)Statins, or HMG-CoA reductase inhibitors, have been shown to reduce cardiovascular events in subjects with or at risk for coronary artery disease. Clinical benefit in trialswith progressively lower baseline and achieved cholesterol levels has led to expanded indications for these medications.Despite robust and consistent results, questions remained about early initiation of statin therapy after acute coronary syndrome (ACS) and whether intensive therapywould result in a greater benefit. Until recently, few data were available on the optimal timing and intensity of initiation of statin therapy after ACS.MIRACLIntensive treatment(atorvastatin mg)Early statinsMiraclA to ZProve ITNRMI

35 Colesterolemia (212-309 mg/dL)The 4S trial was a landmark study that sought to evaluate the effect of statin therapy in secondary prevention. A total of 4,444 men and women with angina or prior MI and serum cholesterol levels of mmol/L ( mg/dL) were randomized to simvastatin (20-40 mg) or placebo for greater than 5 years. Treatment with simvastatin resulted in a 30% relative risk reduction in all-cause mortality (11.5 vs. 8.2%, p<0.001).Colesterolemia ( mg/dL)

36 cholesterol level was <240 mg/dLThe CARE trial sought to evaluate the effect of statins in secondary prevention, particularly among those with average cholesterol levels. The mean total cholesterol level was <240 mg/dL and the LDL-C levels ranged between mg/dL.A total of 4,159 patients with a history of myocardial infarction were randomized to pravastatin (40 mg) or placebo for 5 years. Treatment with pravastatin resulted in a 24% relative risk reduction in the primary end point (myocardial infarction or coronary heart disease death).cholesterol level was <240 mg/dL

37 The LIPID study sought to evaluate the effect of statins in secondary prevention among those with a broad range of cholesterol levels. Patients with a history of known coronary artery disease were randomized to pravastatin (40 mg) or placebo over a mean of 6.1 years. Patients receiving pravastatin experienced a significant 24% relative risk reduction in coronary heart disease mortality, with no clinically significant adverse effects.

38 The Heart Protection Study sought to evaluate the effect of simvastatin on all cause mortality in high risk patients regardless of LDL-C levels. Treatment with simvastatin resulted in a 12% relative risk reduction in all-cause mortality and a 24% relative risk reduction in the first occurrence of any major vascular event. The benefit of simvastatin even extended to individuals with a baseline LDL-C level <100 mg/dL.

44 The MIRACL trial was the first large scale study to evaluate the effects of acute intensive statin therapy in the secondary prevention setting. Compared to placebo, treatment with atorvastatin (80 mg) within 96 hours of an acute coronary syndrome resulted in a 16% relative risk reduction in the primary end point (death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or objective evidence of recurrent symptomatic myocardial ischemia requiring emergency rehospitalization).There were no significant differences in the risk of death, nonfatal myocardial infarction, or cardiac arrest in the two arms of the study. The difference in the primary endpoint was driven by a lower risk of symptomatic ischemia requiring emergency rehospitalization (6.2% vs. 8.4%; RR, 0.74; 95% CI, ; P =0.02). Treatment with atorvastatin resulted in a mean decrease in LDL-C from 124 mg/dL to 72 mg/dL. There was a significant increase in hepatic transaminases >3x the upper limit of normal with atorvastatin as compared to placebo (2.5% vs 0.6%; P<.001).

45 The A to Z trial sought to determine whether treatment with a low dose statin regimen would provide similar risk reduction in patients with an ACS as a high dose statin regimen (similar to that used in the PROVE IT-TIMI 22 and MIRACL trials).The high dose statin regimen consisted of treatment with simvastatin at 40 mg/day for one month, followed by an increase to 80 mg/day thereafter. The low dose statin regimen consisted of treatment with placebo for 4 months, followed by simvastatin at 20 mg/day thereafter.There was no statistical difference in the primary end point between the two treatment strategies; however, there was a trend towards a reduced event rate in the high dose statin regimen at the end of the 24 month follow-up. Unfortunately, the high dose statin regimen was associated with nine cases of statin-induced myopathy.

47 PROVE IT-TIMI 22 was designed to assess the effects of early statin therapy in individuals with an acute coronary syndrome. In a head-to-head comparison of statin regimens, patients were randomized to a high dose potent statin (atorvastatin 80 mg) or a moderate dose less potent statin (pravastatin 40 mg) over a mean follow-up of 24 months to determine if intensive statin therapy was associated with a lower event rate. Use of atorvastatin and pravastatin resulted in on-treatment mean LDL-C levels of 62 mg/dL and 95 mg/dL, respectively.The primary end point (a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, recurrent revascularization, or stroke) occurred in 22.4% of individuals on atorvastatin vs. 26.3% of individuals on pravastatin, p= This effect of intensive statin therapy set a new benchmark for aggressive early LDL-C lowering in acute coronary syndromes.

49 Following the Heart Protection Study, the TNT study sought to determine whether high dose statin therapy provided additional cardiovascular benefit among individuals with chronic coronary heart disease. All patients entered an open-label eight week period with low dose atorvastatin (10 mg) to achieve an LDL-C level <130 mg/dL prior to randomization.Among enrolled patients, high dose atorvastatin (80 mg) resulted in a significant 22% relative risk reduction in the primary composite endpoint (death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke) as compared to low dose atorvastatin (10 mg). Paralleling the reduction in the composite primary endpoint was a decrease in the LDL-C levels to 77 mg/dL and 101 mg/dl in the high and low dose atorvastatin arms, respectively. There were no differences in overall mortality.These results add to the body of data obtained in the PROVE IT-TIMI 22 and HPS trials, demonstrating a benefit with lower LDL-C levels in individuals with coronary heart disease.

54 The HOPE trial sought to evaluate the role of ramipril in patients that were at high risk for cardiovascular events without left ventricular dysfunction or heart failure. The primary outcome was a composite of MI, stroke, or death from cardiovascular causes. A total of 14% of patients taking ramipril reached the primary end point, as compared with 18% of patients assigned to receive placebo (RR 0.78; ; P<0.001).Treatment with ramipril reduced the rates of death from cardiovascular causes (6%, vs. 8%; RR 0.74; P<0.001), MI (10% vs. 12%; RR 0.80; P<0.001), stroke (3.4% vs. 5%; RR 0.68; P<0.001), death from any cause (10% vs. 12%; RR 0.84; P=0.005), revascularization procedures (16% vs. 18%;RR 0.85; P=0.002), cardiac arrest (0.8% vs. 1.3%; RR 0.63; P=0.03), heart failure (9% vs. 11.5%; RR 0.77; P<0.001), and complications related to diabetes (6% vs. 8%; RR 0.84; P=0.03).Treatment with ramipril was associated with a significant reduction in the rates of death, MI, and stroke in a broad range of high-risk patients that were not known to have left ventricular systolic dysfunction or heart failure.Studio interrotto anticipatamente per chiara e significativa riduzione di mortalità nel gruppo ramipril.Nei diabetici il beneficio è stato ancora più evidente.

55 This trial assessed whether perindopril reduced cardiovascular risk in an intermediate-risk population with stable coronary heart disease and no apparent heart failure. After a run-in period of 4 weeks in which all patients received perindopril, 12,218 patients were randomly assigned perindopril 8 mg once daily (n=6110) or matching placebo (n=6108). The mean follow-up was 4.2 years and the primary end point by an intention to treat analysis was cardiovascular death, myocardial infarction, or cardiac arrest.A majority of patients were already on antiplatelet agents, a beta-blocker, and lipid lowering therapy. Perindopril resulted in a 20% relative risk reduction in the primary endpoint compared to placebo (95% Cl 9–29, p=0.0003). These benefits were consistent in all prespecified subgroups and secondary end points.This led the investigators to conclude that among patients with stable coronary heart disease without apparent heart failure, perindopril resulted in significantly improved outcomes and a reduction of one major cardiovascular event for every 50 patients treated over 4 years.

56 The PEACE Trial was designed to test the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy.The incidence of the primary end point (death from cardiovascular causes, myocardial infarction, or coronary revascularization) was 21.9% in the trandolapril group, as compared with 22.5% in the placebo group (hazard ratio in the trandolapril group, 0.96; 95 percent CI, 0.88 to 1.06; P=0.43) over a median follow-up period of 5 years.This led the authors to conclude that in patients with stable coronary artery disease and preserved left ventricular systolic function that are receiving "current standard" therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor is associated with further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization. Trandolapril at this dose, however, did slow progression from the metabolic syndrome to diabetes.

58 In these three post-infarction trials (n=5966), mortality was lower with ACE inhibitors than with placebo (odds ratio 0.74 [95% Cl 0.66–0.83]), as were the rates of readmission for heart failure (OR 0.73 [0.63–0.85]), re-infarction (OR 0.80 [ ]) or the composite of these events (OR 0.75 [0.67–0.83]; all p<0.001).The benefits were observed early after the start of therapy and persisted long term. The benefits were independent of age, sex, and baseline use of diuretics, aspirin, and β-blockers. Although there was a trend towards greater reduction in risk of death or readmission for heart failure in patients with lower ejection fractions, the benefit extended over the range of ejection fractions examined.This led the authors to conclude that ACE inhibitors lower rates of mortality, myocardial infarction, and hospital admission for heart failure in patients with left-ventricular systolic dysfunction or heart failure following a MI.

61 B ACE Inhibitor RecommendationsAHA/ACC Secondary Prevention for Patients with Coronary Artery and Other Atherosclerotic Vascular DiseaseACE Inhibitor RecommendationsUse in all patients with LVEF < 40%, and those with diabetes or chronic kidney disease indefinitely, unless contraindicatedConsider for all other patientsAmong lower risk patients with normal LVEF where cardiovascular risk factors are well controlled and where revascularization has been performed, their use may be considered optionalIIIaIIbIIIBACE=Angiotensin converting enzyme, LVEF= left ventricular ejection fractionCirculation 2006;113: andJ Am Coll Cardiol 2006;47:

63 This double-blind trial compared the effect of an angiotensin-receptor blocker (valsartan), to an ACE inhibitor (captopril), and the combination of the two on mortality in patients with post-infarction heart failure or left ventricular systolic dysfunction.During a median follow-up of 24.7 months, there was no difference in all cause mortality between the three groups. The upper limit of the one-sided 97.5% confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001).The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group.These findings led the authors to conclude that valsartan was as effective as captopril in patients that are at high risk for cardiovascular events after myocardial infarction and that combining valsartan with captopril increased the rate of adverse events without improving survival.

64 Angiotensin Receptor Blocker RecommendationsAHA/ACC Secondary Prevention for Patients with Coronary Artery and Other Atherosclerotic Vascular DiseaseAngiotensin Receptor Blocker RecommendationsUse in patients who are intolerant of ACE inhibitors with HF or post MI with LVEF less than or equal to 40%.Consider in other patients who are ACE inhibitor intolerant.Consider use in combination with ACE inhibitors in systolic dysfunction HF.IIIaIIbIIIACE=Angiotensin converting enzyme inhibitor, LVEF=Left Ventricular Ejection fraction, HF=Heart failure, MI=Myocardial infarctionCirculation 2006;113: andJ Am Coll Cardiol 2006;47:

66 Omega 3 fatty acid supplementation appears to lower CV events in several large clinical trials.In the Diet and Reinfarction Trial (DART), 2033 men with a history of MI received one of three dietary recommendations: (a) reduced fat and increased ratio of polyunsaturated to saturated fat, (b) increased fatty fish intake, or (c) increased fiber intake. The fish group was advised to eat at least 2 portions of fatty fish (300 grams total), corresponding to a weekly intake of about 2.5 grams of eicosapentaenoic acid (EPA). Those who could not tolerate this fish intake were advised to supplement it with fish oil capsules. Those advised to eat fatty fish had a 29% relative decrease in two year all-cause mortality compared with the other two groups.The GISSI trial randomized 11,324 patients with a history of MI to n-3 polyunsaturated fatty acids (PUFA) (1 gram daily), vitamin E (300 mg daily), both, or none for 3.5 years. n-3 PUFA, but not vitamin E, significantly lowered the risk of the primary end point (a composite of death, nonfatal MI, and stroke). n-3 PUFA decreased the relative risk of the primary end point by 15% in four-way analysis (p=0.023). Of note, the dose of n-3 PUFA used in this study (1 gram daily) is the dose recommended for patients with coronary heart disease, but is lower than the dose approved for triglyceride lowering (2-4 gram daily).